Friday, June 1, 2012
These are exciting times in ovarian cancer research. We just attended the Canadian Conference on Ovarian Cancer Research (CCOCR http://www.ccocr.org/) in Quebec City, Quebec, Canada and the theme of the conference was “Where there is a molecular path, there is a way.” Surprisingly there were only three or four presentations which utilized animal models, the rest of the conference including oral, poster and plenary talks were based on clinical research. The further analysis of ovarian cancer subtypes and defining each of the subtypes by their genomic signatures, phenotypic and morphological features, and anatomical location to give insight into the potential site from which the cancers originate, but more importantly, to devise effective “personalized” therapies. It now appears that ovarian cancer may be described as possibly 8 distinct cancers. Impressive technology is being brought to bear on this disease. The use of next-generation, massively parallel deep sequencing of the tumors brings new insight into the complex changes underlying the cancers. Instead of considering the cancers from the viewpoint of single gene mutations, it is clear that pathways instead of individual genes need to be targeted. Combined targeted therapies are bringing improved patient outcomes—but these are often marginal gains. Increasing progression free survival by 3 months is still considered a major therapeutic advance. Beyond gene signatures, investigations reveal alteration in copy number of certain genes and specific chromosomal rearrangements. Certain of these cancer subtypes feature considerable genomic instability, especially the biggest killer of them all, “high grade serous” cancer—of which more than 70% of ovarian cancer victims succumb.
Yet lacking from these enlightened discussions and state-of-the art technological advances is an increase in our understanding of the underlying cause of ovarian cancer. While it appears that the fimbriae of the Fallopian tube is the origin of high grade serous cancers which are proposed to spread from tube to ovary to the peritoneum, it remains an open question—what event caused the neoplastic transformation in the first place? The so called incessant ovulation hypothesis, proposed in 1971 by Fathalla is no longer favored by the gynecologic oncologists, largely because of the postulate that the ovarian surface epithelium the OSE is the origin of the disease. This idea is challenged the evidence that serous disease my arise from the tubal epithelium, and also the emerging idea that other forms of the disease may arise from endometriosis associated lesions. The gifted gynecologic surgeons who are “debulking” these cancers observe the similarity in appearance and presentation of the endometrioid cancer with the endometriomas and propose a causal relationship. The molecular signature of the endometrial cancers and the endometrioid ovarian tumors supports the clonal origins of the disease and help the physicians devise targeted combinatorial therapies for the afflicted women.
We still favor the basic postulate set forth in the incessant ovulation hypothesis—that ovulation is an inflammatory event and the associated oxidative stress and inflammation is the molecular insult that initiates the transformation. The endometriosis origin when examined carefully also supports inflammation as the prime driver of the disease—moreover, only endometriomas are associated with endometrioid type of ovarian cancer, and these are endometriosis lesions on the ovary itself—so called “chocolate cysts.” The fimbriae is in close physical proximity to the surface of the ovary and the insult associated with ovulation exposes the tubal epithelium to the same inflammatory milieu as the OSE. Tubal, endometriotic or ovarian surface—the inflammatory insult is the common culprit.
Chemoresistance, recurring disease, poor prognosis—all the unfortunate hallmarks of ovarian cancer. Molecular medicine advances the therapeutic options and outcomes are improving. Yet there is no better cure for the disease than prevention. And here is probably the single most important feature of the chicken model of ovarian cancer—it provides the opportunity to devise effective interventions that are potentially able to prevent the disease in the first place. Furthermore, the hens provide us with a tool to look at the very first initiating events. What prevents ovarian cancer? Reducing the number of life time ovulations is the best intervention thus far described. Parity, breast feeding, steroidal contraceptives—all lead to significant reductions in cancer incidence. Reducing the inflammation associated with ovulation maybe another effective preventative. Also reducing the inflammation associated with endometriosis is also likely to have important effects on ovarian cancer reduction. And we propose that dietary intervention with natural foods rich in antioxidants with anti-inflammatory properties will provide the population with a significant reduction in ovarian cancers when adopted. This hypothesis has substantial support from dietary intervention studies in hens, and provides the foundation for clinical trials in women.